The antitumor agent paclitaxel shows increased efficacy and decreased toxicity when administered to tumor-bearing hosts as a polyglutamic acid conjugate compared with the unconjugated form of the drug (U.S. Pat. No. 5,977,163; Li et al., Cancer Res., 58:2404, 1998). The polyglutamic acid-paclitaxel conjugate shows increased water solubility, a slower clearance from the body, and an increased accumulation in the tumor. Conjugates of polyglutamic acid and various other therapeutic agents are expected to provide clinically useful alternatives to the presently available formulations.
For research purposes, the polyglutamic acid-therapeutic agent conjugates can be produced by the method disclosed in Li et al., ibid. In that method, the conjugate is prepared as a sodium salt, dialyzed to remove low molecular weight contaminants and excess salt and then lyophilized. The method is not well-suited for large-scale manufacture of quantities of conjugates for clinical development and use, however. In particular, the use of dialysis to remove impurities is time-consuming and lowers final product yield. In addition, although many pharmaceuticals have more favorable properties when prepared as salts (e.g., improved solubility, storage, and handling), this is not true of the polyglutamate-therapeutic agent conjugates of the present invention. The salt forms of the conjugates are electrostatic solids, not free flowing powders. They are more difficult to package, more susceptible to dust contamination and more likely to contaminate the workplace with cytotoxic agents than are free flowing powders. Therefore, there is a need for an improved process of manufacture of polyglutamic acid-therapeutic agent conjugates that can be used to produce gram to hundreds of gram quantities of these conjugates in high yields and in a manner that provides for improved materials handling and packaging.